Organolithium and lithium amide compounds are important reagents used routinely in synthetic chemistry transformations. Traditionally, organolithium reagents are made by combining finely divided lithium metal at low temperature with solutions of haloorganics or by metal-halogen exchange reactions. Lithium amides are most commonly prepared by the deprotonation of amines using an organolithium reagent. However, stability, storage, and handling of organolithium compounds remain problems that often make their use difficult for organic synthesis, including their use to make lithium amides.
Organolithium as used herein, and as commonly used in the art, refers to lithium compounds of carbon-centered anions. Organolithium reagents are synthetically useful because they are strong bases, effective nucleophiles, and effective catalysts for radical and anionic polymerizations. Such reagents are, however, very reactive, often spontaneously catching fire in the presence of air. To control these hazards, they are only commercially available as solutions in hydrocarbon or ether solvents. These solvents can moderate the pyrophoric nature of the organolithiums, but are themselves volatile and flammable, adding further hazards associated with the use of organolithium reagents.
Lithium amide, as used herein, refers to lithium salts of primary and secondary amines. Lithium amide reagents are synthetically useful because they are strong bases, freely soluble in common organic solvents, and highly versatile. These reagents are, however, very reactive and difficult to handle. With some exceptions, they are not available commercially and must be synthesized immediately prior to their use by adding a primary or secondary amine to an organolithium reagent, such as butyllithium.
Lithium metal is commonly used to generate an organolithium reagent, which is an organometallic compound with a direct bond between a carbon and a lithium atom. Since the electropositive nature of lithium places most of the charge density of the bond on the carbon atom, a carbanion species is created. This enables organolithium reagents to act as extremely powerful bases and nucleophiles. Typically, organolithium reagents are synthesized commercially by the reaction of a haloorganic with lithium metal, according to R—X+2Li→R—Li+LiX (See U.S. Pat. No. 5,523,447 by Weiss et al. and U.S. Patent Application Publication No. 20060049379 by Emmel et al). A side reaction that occurs during this synthesis, especially with alkyl iodides, is the Wurtz reaction, where the R group couples with itself. This side reaction can be nearly eliminated by using cold temperatures or chlorine or bromine as the halogen. Other methods of creating organolithium reagents include, for example: (i) reacting a organic halide with a radical anion lithium salt, (ii) performing a metal-halogen exchange between an organic halogen compound and an organolithium species (e.g., Gilman, H. et. al., J. Am. Chem. Soc. 1932; 54, 1957), (iii) an exchange between an organolithium species and another organometallic compound, (iv) the deprotonation of an organic compound with an organolithium reagent, (v) reductive cleavage of the carbon-heteroatom (such as sulfur, oxygen, phosphorus, or silicon) bonds (e.g., Gilman. H., et. al., Org. Chem. 1958; 23, 2044), or (vi) lithium-hydrogen exchange from LiOH and toluene to make benzyl lithium in DMSO (U.S. Patent Application Publication No. 20060170118 by Everett et. al.).
Organolithium reagents, specifically butyllithium (BuLi), methyllithium (MeLi), phenyllithium (PhLi), and others, are widely used as chemical building blocks and as strong bases in both the pharmaceutical and the industrial manufacturing industry. Lithium amides find related applications; for example, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS) are both strong bases that are also capable of performing enantioselective alkylation by virtue of the strong coordinating ability of lithium (Hilpert, H. Tetrahedron, 2001, 57, 7675). Carbon-centered organolithiums, such as nBuLi, are considered to be both powerful nucleophiles and strong bases at the same time. (Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R, A.; Volante, R. P.; Shinkai, I. J. Org. Chem. 1992, 57, 2771). These characteristics enable their use as initiators for anionic polymerizations (Hungenberg, Klaus-Dieter; Loth, Wolfgang; Knoll, Konrad; Janko, Lutz; Bandermann, Friedhelm. Method for producing statistical styrene-butadiene copolymers. PCT Int. Appl. WO 9936451 A1.
Little can be done to modify the reactivity or selectivity of ordinary organolithium and lithium amide reagents, yet modification is a growing need in many chemical industries, especially for pharmaceutical and polymerization processes. Traditional stir-batch modes of synthesis with either of these types of compounds generate significant quantities of solvent waste, which is undesirable for any chemical process. A cleaner process, which would involve either a solvent-free organolithium or lithium amide material or a packed-bed flow reactor setup, would be ideal for large scale industrial synthesis, as it would decrease solvent disposal issues and might eliminate tedious purification or work-up steps. One solution would be the creation of a solid source of organolithium reagents which could be used in flow chemistry and would control the efficiency and effectiveness of the reagent in a process. This notion has spawned efforts to develop crystalline Grignard reagents (Marcus, V., et. al. Angew Chem, Int. Ed. 2000, 39, 3435) and other solid carbanion sources (Davies, S. G. et. al. J. Am. Chem. Soc. 1977, 4, 135 and Eaborn, C., et. al. J. Am. Chem. Soc. 1994, 116, 12071) in recent years. However, the methods of preparation of these crystalline reagents are typically tedious and specialized for specific carbanion systems, limiting their utility in large-scale applications and their applicability as general carbanion sources. Grignard reagents, the broadest class of carbanion donors, furthermore undergo the Schlenk equilibrium between two equivalents of an alkyl or aryl magnesium halide (2 RMgX) and one equivalent each of the dialkyl- or diarylmagnesium compound (RMgR) and the magnesium halide salt (MgX2). This disproportionation reaction multiplies the reactive species present, and is a sometimes problematic complication in their applications as carbanion sources.
Only a few of the known organolithium compounds, such as butyllithium, methyllithium, and phenyllithium, are commercially available. Many organolithiums that are not commercially available must be prepared from metal-halogen exchange reactions (for a general reference, see Wakefield, B. Organolithium Methods; Academic Press: London, 1988) that use one organolithium reagent and an organic halide in an exchange reaction. Alternatively, pure lithium metal and an organic halide can be reacted to form an organolithium. These transformations represent equilibrium reactions between organic halides, lithium metal, lithium halides and organolithium compounds. Synthesizing a clean organolithium product is difficult since there is often contamination with unreacted organic halides, which adds hardship to any large scale process development. Lithiation can also be performed by deprotonation reactions or by reductive cleavage of ethers and thioethers (Schlosser, M. Organometallics in Syntheses; Wiley and Sons: Chichester, 1994, 47), the Shapiro method (Shapiro, R. H. Org. React. 1976, 23, 405), or arene-catalyzed lithiation (Yus, M.; Ramon, D. J.; J. Chem. Soc., Chem. Commun. 1991, 398). These methods begin by utilizing organolithium itself, functioning as a base, and therefore they are not atom-economic from a synthetic standpoint. The approach of directly reacting lithium metal with the halogenated form of the target organic group is strongly avoided in most industries because of the high reactivity and pyrophoric nature of finely divided Li metal. Dispersed lithium prepared in a refluxing hydrocarbon also causes hardship in large scale ups (Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P. Org. Process Res. Dev.; 2005; 9(6); 997-1002.). Alternatively, mercury-lithium (Schollkopf, U.; Gerhart, F. Angew. Chem. Int. Ed. Engl. 1981, 20, 795), tellurium lithium (Shiner, C. S.; Berks, A. H.; Fisher, A. M. J. Am. Chem. Soc. 1988, 110, 957, Hiiro, T.; Mogami, T.; Kambe, N.; Fujiwara, S-I.; Sonoda, N. Synth. Commun. 1990, 20, 703) and tin-lithium (Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346) mediated transmetallations are also possible, but mercury, tellurium and tin compounds are generally toxic, making these reagents unsuitable for large scale industrial processes.
In a different strategy from the present invention, alkyllithiums (MeLi, EtLi) are stabilized by adsorbing the alkyllithium onto the surface of a nonporous inorganic support, such as SiO2, CaO, or Al2O3, and then coated with a paraffin wax (Deberitz et al. U.S. Pat. No. 5,149,889). However, in this case, one has to use pre-made alkyllithium reagents. Then, to activate the reactivity, the user must remove the oil, wax, or hydrocarbon, which can add another undesirable separation step. An additional major difference from the current invention is the fact that the alkyllithium is adsorbed onto the surface of the inorganic support, not absorbed into the support. This strategy highlights the chemical industry's need and desire for stabilized and easily useable alkyllithium reagents.
Like organolithium compounds, lithium amides have a limited commercial availability. While they can be prepared with difficulty from lithium and a primary or secondary amine, they are most conveniently prepared by treatment of a primary or secondary amine with an organolithium reagent. Thus, lithium amide use suffers from many of the same limitations as the organolithium reagents from which they are typically derived. The three most common organolithium reagents used for generating lithium amides are methyllithium, butyllithium, and phenyllithium, which produce methane, butane, and benzene respectively during the reaction. All of these byproducts pose drawbacks in a manufacturing environment since they are all volatile, flammable materials. Methane and butane are flammable gases at room temperature and their generation as stoichiometric byproducts in large scale manufacturing is problematic and costly. Benzene is toxic and a known carcinogen.
A need exists, therefore, to have organolithium and lithium amide reagents available in a dry form that may be easily handled, stored, and used without a significant loss of their reactivity. This invention answers that need.